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Population pk

Miriam Krischke, Georg Hempel, Swantje Völler, Nicolas André, Maurizio D'Incalci, Gianni Bisogno, Wolfgang Köpcke, Matthias Borowski, Ralf Herold, Alan V Boddy, Joachim Boos
PURPOSE: Doxorubicin is a key component in many pediatric oncology treatment regimens; still pharmacology data on which current dosing regimens are based are very limited. METHODS: We conducted a multinational pharmacokinetic study investigating age dependency of doxorubicin metabolism and elimination in children with cancer. One hundred and one patients treated with doxorubicin according to a cancer-specific national or European therapeutic trial were recruited...
October 21, 2016: Cancer Chemotherapy and Pharmacology
Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, Saik Urien, Sihem Benaboud
BACKGROUND: Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. METHODS: A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK)...
October 21, 2016: Clinical Pharmacokinetics
Man-Chiu Poon, Adrienne Lee
Prophylaxis is considered optimal care for hemophilia patients to prevent bleeding and to preserve joint function thereby improving quality of life (QoL). The evidence for prophylaxis is irrefutable and is the standard of care in developed nations. Prophylaxis can be further individualized to improve outcomes and cost effectiveness. Individualization is best accomplished taking into account the bleeding phenotype, physical activity/lifestyle, joint status, and pharmacokinetic handling of specific clotting factor concentrates, all of which vary among individuals...
2016: Thrombosis Journal
Lawrence C Ku, Huali Wu, Rachel G Greenberg, Kevin D Hill, Daniel Gonzalez, Christoph P Hornik, Alysha Berezny, Jeffrey T Guptill, Wenlei Jiang, Nan Zheng, Michael Cohen-Wolkowiez, Chiara Melloni
BACKGROUND: Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. METHODS: Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free)...
October 19, 2016: Therapeutic Drug Monitoring
Ling Xue, Nick Holford, Xiao-Liang Ding, Zhen-Ya Shen, Chen-Rong Huang, Hua Zhang, Jing-Jing Zhang, Zhe-Ning Guo, Cheng Xie, Ling Zhou, Zhi-Yao Chen, Lin-Sheng Liu, Li-Yan Miao
AIMS: The aims of this study are to apply a theory based mechanistic model to describe the pharmacokinetics (PK) and pharmacodynamics (PD) of S- and R-warfarin. METHODS: Clinical data were obtained from 264 patients. Total concentrations for S- and R-warfarin were measured by ultra-high performance liquid tandem mass spectrometry. Genotypes were measured using pyrosequencing. A sequential population pharmacokinetic parameter with data method was used to describe the international normalized ratio (INR) time course...
October 20, 2016: British Journal of Clinical Pharmacology
Xu Steven Xu, Min Yuan, Haitao Yang, Yan Feng, Jinfeng Xu, Jose Pinheiro
Covariate analysis based on population pharmacokinetics (PPK) is used to identify clinically relevant factors. The likelihood ratio test (LRT) based on nonlinear mixed effect model fits is currently recommended for covariate identification, whereas individual empirical Bayesian estimates (EBEs) are considered unreliable due to the presence of shrinkage. The objectives of this research were to investigate the type I error for LRT and EBE approaches, to confirm the similarity of power between the LRT and EBE approaches from a previous report and to explore the influence of shrinkage on LRT and EBE inferences...
October 19, 2016: AAPS Journal
Prashant Trikha, Robert L Plews, Andrew Stiff, Shalini Gautam, Vincent Hsu, David Abood, Robert Wesolowski, Ian Landi, Xiaokui Mo, John Phay, Ching-Shih Chen, John Byrd, Michael Caligiuri, Susheela Tridandapani, William Carson
Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. MDSC play a critical role during tumor evasion and promote immune suppression through variety of mechanisms, such as the generation of reactive oxygen and nitrogen species (ROS and RNS) and cytokines. AMPactivated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that regulates energy homeostasis and metabolic stress. However, the role of AMPK in the regulation of MDSC function remains largely unexplored...
2016: Oncoimmunology
Eunchong Park, Ju Han Song, Myun Soo Kim, Su-Ho Park, Tae Sung Kim
CD4(+) T cell activation and adequate differentiation into effector T helper (Th) cells are crucial for mediating adaptive immune responses to cope with foreign pathogens. Despite the significant role of Th cells, excessive increases in their numbers result in inflammatory and autoimmune diseases. In this study, we investigated the effects of costunolide, a plant-derived natural compound with an anti-inflammatory activity, in regulating Th cells and the underlying mechanisms. Costunolide significantly decreased cell populations of differentiated Th1, Th2, and Th17 subsets under Th subset-polarizing conditions, while exerting statistically negligible effects on Treg cell differentiation...
October 15, 2016: International Immunopharmacology
Y K Lyauk, C Stage, T K Bergmann, L Ferrero-Milliani, D Bjerre, R Thomsen, K P Dalhoff, H B Rasmussen, G Jürgens
The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d-MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two-compartment disposition model with absorption transit compartments...
October 18, 2016: Clinical and Translational Science
Dong-Seok Yim
In the early phase of clinical development of antihypertensive drugs, quantitative modeling to predict their dose-concentration-response relationship is important to plan future clinical development and finding optimal dosage regimen at marketing approval. Two cases of concentration-response models of antihypertensive are presented here.Case 1: Carvedilol is a α1- and nonselective β- adrenergic receptor antagonist currently used for the management of mild-to-moderate essential hypertension and congestive heart failure...
September 2016: Journal of Hypertension
Alexandra Staikou, Evagelia Kesidou, Marina-Elena Garefalaki, Basile Michaelidis
Land snails species occur in a range of habitats from humid to semi-arid and arid ones and seasonal variations in their physiology and biochemical composition have been linked to annual cycles of photoperiod, temperature, humidity and water availability. In an effort to understand the thermal tolerance and the impact of temperature elevation on tissue metabolism of land snails we determined the mortality, heamolymph PO2 and the activities of enzymes of intermediary metabolism in three land snail species (Helix lucorum, Helix pomatia and Cornu aspersum) differing in their geographical distribution and inhabiting areas with different climatic characteristics...
October 14, 2016: Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology
Ying Zhang, Xiaoyu Guo, Juan Dong
Cell polarization is commonly used for the regulation of stem cell asymmetric division in both animals and plants. Stomatal development in Arabidopsis, a process that produces breathing pores in the epidermis, requires asymmetric cell division to differentiate highly specialized guard cells while maintaining a stem cell population [1, 2]. The BREAKING OF ASYMMETRY IN THE STOMATAL LINEAGE (BASL) protein exhibits a polarized localization pattern in the cell and is required for differential cell fates resulting from asymmetric cell division [3]...
October 5, 2016: Current Biology: CB
Saif Ullah, Rizwan Mustafa Shah, Sarfraz Ali Shad
Dusky cotton bug (DCB), Oxycarenus hyalinipennis (Lygaeidae: Hemiptera) is a serious pest of cotton and other malvaceous plants. Chlorfenapyr, a broad spectrum, N-substituted, halogenated pyrrole insecticide is used extensively to control many insect pests in cotton, including DCB. In this study, we investigated a field strain of DCB to assess its potential to develop resistance to chlorfenapyr. After six generations of continuous selection pressure with chlorfenapyr, DCB had a 7.24-fold and 149.06-fold resistance ratio (RR) at G1 and G6, respectively...
October 2016: Pesticide Biochemistry and Physiology
Hannes Schmidt, Stefanie Peters, Katharina Frank, Lai Wen, Robert Feil, Fritz G Rathjen
A cGMP signaling pathway, comprising C-type natriuretic peptide (CNP), its guanylate cyclase receptor Npr2, and cGMP-dependent protein kinase I (cGKI), is critical for the bifurcation of dorsal root ganglion (DRG) and cranial sensory ganglion axons when entering the mouse spinal cord and the hindbrain, respectively. However, the identity and functional relevance of phosphodiesterases (PDEs) that degrade cGMP in DRG neurons are not completely understood. Here we asked whether regulation of the intracellular cGMP concentration by PDEs modulates the branching of sensory axons...
October 14, 2016: European Journal of Neuroscience
Savitha Varatharajan, John C Panetta, Ajay Abraham, Sreeja Karathedath, Ezhilpavai Mohanan, Kavitha M Lakshmi, Nancy Arthur, Vivi M Srivastava, Sandeep Nemani, Biju George, Alok Srivastava, Vikram Mathews, Poonkuzhali Balasubramanian
PURPOSE: Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors, including the pharmacokinetics (PK) of Cytarabine (Ara-C) and Daunorubicin (Dnr), could contribute to difference in treatment outcome in AML. METHODS: In the present study, we evaluated the plasma PK of Dnr, the influence of genetic polymorphisms of genes involved in transport and metabolism of Dnr on the PK, and also the influence of these factors on clinical outcome...
October 13, 2016: Cancer Chemotherapy and Pharmacology
Akwugo A Eziefule, Solafa Elshatanoufy, Mili Thakur, Frederico G Rocha
Background Propofol is a widely known, commonly used drug. Complications can occur with the use of this drug, including propofol-related infusion syndrome (PRIS). PRIS, in the obstetric population, has not been documented; however, we report a case of a patient who developed PRIS after an emergent cesarean delivery of a preterm infant. Case Study A 35-year-old multigravida woman presented complaining of leakage of fluid and decreased fetal movement. Her pregnancy was complicated by methadone maintenance therapy due to a history of opioid abuse...
October 2016: American Journal of Perinatology Reports
A Mercuri, S Wu, S Stranzinger, S Mohr, S Salar-Behzadi, M Bresciani, E Fröhlich
This work aims to better understand the in vivo behaviour of modified release (MR) formulations (Envarsus(®) tablets and Advagraf(®) capsules) using in vitro properties of tacrolimus and in silico simulations. The in silico concentration profiles of tacrolimus released from the MR formulations were predicted after building a three compartments PK model with GastroPlus™, and using the experimentally determined in vitro physico-chemical properties as input parameters. In vitro-in vivo correlations (IVIVC) were obtained after deconvolution of in vivo data from a clinical trial...
October 11, 2016: International Journal of Pharmaceutics
M Moore, S Gill, T Asmis, S Berry, R Burkes, K Zbuk, T Alcindor, A Jeyakumar, T Chan, S Rao, J Spratlin, P A Tang, J Rothenstein, E Chan, J Bendell, F Kudrik, J Kauh, S Tang, L Gao, S R P Kambhampati, F Nasroulah, L Yang, N Ramdas, P Binder, E Strevel
BACKGROUND: Icrucumab and ramucirumab are recombinant human IgG1 monoclonal antibodies that bind VEGF receptors 1 and 2 (VEGFR-1 and -2), respectively. This randomized phase II study evaluated the antitumor activity and safety of icrucumab and ramucirumab each in combination with mFOLFOX-6 in patients with metastatic colorectal cancer after disease progression on first-line therapy with a fluoropyrimidine and irinotecan. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive mFOLFOX-6 alone (mFOLFOX-6) or in combination with ramucirumab 8 mg/kg IV (RAM+mFOLFOX-6) or icrucumab 15 mg/kg IV (ICR+mFOLFOX-6) every 2 weeks...
October 11, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Rodrigo Dutra Nunes, Guilherme Ventura-Martins, Débora Monteiro Moretti, Priscilla Medeiros-Castro, Carlucio Rocha-Santos, Carlos Renato de Oliveira Daumas-Filho, Paula Rego Barros Bittencourt-Cunha, Karina Martins-Cardoso, Cecília Oliveira Cudischevitch, Rubem Figueiredo Sadok Menna-Barreto, José Henrique Maia Oliveira, Desiely Silva Gusmão, Francisco José Alves Lemos, Daniela Sales Alviano, Pedro Lagerblad Oliveira, Carl Lowenberger, David Majerowicz, Ricardo Melo Oliveira, Rafael Dias Mesquita, Georgia Correa Atella, Mário Alberto Cardoso Silva-Neto
BACKGROUND: Mosquitoes feed on plant-derived fluids such as nectar and sap and are exposed to bioactive molecules found in this dietary source. However, the role of such molecules on mosquito vectorial capacity is unknown. Weather has been recognized as a major determinant of the spread of dengue, and plants under abiotic stress increase their production of polyphenols. RESULTS: Here, we show that including polyphenols in mosquito meals promoted the activation of AMP-dependent protein kinase (AMPK)...
October 2016: PLoS Neglected Tropical Diseases
Hannah C Slater, Lucy C Okell, Azra C Ghani
Mathematical models of the dynamics of a drug within the host are now frequently used to guide drug development. These generally focus on assessing the efficacy and duration of response to guide patient therapy. Increasingly, antimalarial drugs are used at the population level, to clear infections, provide chemoprevention, and to reduce onward transmission of infection. However, there is less clarity on the extent to which different drug properties are important for these different uses. In addition, the emergence of drug resistance poses new threats to longer-term use and highlights the need for rational drug development...
October 7, 2016: Trends in Parasitology
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